Risk of Non-Melanoma Cancers in First-Degree Relatives of CDKN2A Mutation Carriers
Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.Journal of the National Cancer Institute (Impact Factor: 12.58). 04/2012; 104(12):953-6. DOI: 10.1093/jnci/djs221
The purpose of this study was to quantify the risk of cancers other than melanoma among family members of CDKN2A mutation carriers using data from the Genes, Environment and Melanoma study. Relative risks (RRs) of all non-melanoma cancers among first-degree relatives (FDRs) of melanoma patients with CDKN2A mutations (n = 65) and FDRs of melanoma patients without mutations (n = 3537) were calculated as the ratio of estimated event rates (number of cancers/total person-years) in FDRs of carriers vs noncarriers with exact Clopper-Pearson-type tests and 95% confidence intervals (CIs). All statistical tests were two-sided. There were 56 (13.1%) non-melanoma cancers reported among 429 FDRs of mutation carriers and 2199 (9.4%) non-melanoma cancers in 23 452 FDRs of noncarriers. The FDRs of carriers had an increased risk of any cancer other than melanoma (56 cancers among 429 FDRs of carrier probands vs 2199 cancers among 23 452 FDRs of noncarrier probands; RR = 1.5, 95% CI = 1.2 to 2.0, P = .005), gastrointestinal cancer (20 cancers among 429 FDRs of carrier probands vs 506 cancers among 23 452 FDRs of noncarrier probands; RR = 2.4, 95% CI = 1.4 to 3.7, P = .001), and pancreatic cancer (five cancers among 429 FDRs of carrier probands vs 41 cancers among 23 452 FDRs of noncarrier probands; RR = 7.4, 95% CI = 2.3 to 18.7, P = .002). Wilms tumor was reported in two FDRs of carrier probands and three FDRs of noncarrier probands (RR = 40.4, 95% CI = 3.4 to 352.7, P = .005). The lifetime risk of any cancer other than melanoma among CDKN2A mutation carriers was estimated as 59.0% by age 85 years (95% CI = 39.0% to 75.4%) by the kin-cohort method, under the standard assumptions of Mendelian genetics on the genotype distribution of FDRs conditional on proband genotype.
Article: Genetic Testing by Cancer Site[Show abstract] [Hide abstract]
ABSTRACT: It is estimated that 5% to 10% of pancreatic cancer is familial. Although there is evidence of a major pancreatic cancer susceptibility gene, the majority of families with multiple cases of pancreatic cancer do not have an identifiable causative gene or syndrome. However, a subset of pancreatic cancer is attributable to known inherited cancer predisposition syndromes, including several hereditary breast cancer genes (BRCA1, BRCA2, and PALB2), CDKN2A, hereditary pancreatitis, hereditary nonpolyposis colorectal cancer, and Peutz-Jeghers syndrome. In addition to explaining a proportion of familial pancreatic cancer, individuals with these conditions are at increased risk for pancreatic cancer. Relatives from familial pancreatic cancer kindreds without one of these identifiable syndromes may have as high as a 32-fold risk of pancreatic cancer, depending on the number of affected first-degree relatives. Such high-risk individuals may benefit from increased surveillance, and strategies for early detection of pancreatic cancer are under evaluation.The Cancer Journal 07/2012; 18(4):350-4. DOI:10.1097/PPO.0b013e3182624694 · 4.24 Impact Factor
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ABSTRACT: A comprehensive family history is essential to identify patients at risk for hereditary cancer who could benefit from genetic counseling (GC). In a previous study, we observed a low occurrence of family history record (FHR) collection rate and GC referral among oncologists at our institution. The present work analyzes whether the implementation of a heredofamilial cancer unit (HFCU) would improve these parameters. We retrospectively compared the FHR rate in clinical records, National Cancer Institute (NCI) general criteria for hereditary cancer suspicion, GC referrals and FHR quality in two cohorts: cohort 1 (patients diagnosed before HFCU creation) and cohort 2 (after HFCU creation). Of 1,175 patients (590 cohort 1 and 585 cohort 2), FHRs were consigned in 27.3 % and 52.5 % of patients, respectively (p < 0.001). The GC referral of patients with any NCI criterion was 13.6 % xin cohort 1 vs. 40.5 % in cohort 2 (p < 0.001). FHR quality improved in terms of the total number of relatives (164 vs. 314, p = 0.1, N.S.) and number of healthy relatives consigned (80 vs. 191, p < 0.01). Nine mutations (6 BRCA, 1 MEN1, 2 Lynch), 4 unknown significance variants (all in BRCA) and 2 with no mutation were identified among patients referred from cohort 2. We conclude that the creation of a heredofamilial cancer unit has changed both FHR and GC referrals among oncologists at our institution, although continuous educational efforts are required.Journal of Genetic Counseling 06/2013; 23(1). DOI:10.1007/s10897-013-9617-z · 2.24 Impact Factor
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ABSTRACT: Background Germline mutations in the tumour suppressor gene CDKN2A occur in 5–20% of familial melanoma cases. A single founder mutation, p.Arg112dup, accounts for the majority of CDKN2A mutations in Swedish carriers. In a national program, carriers of p.Arg112dup mutation have been identified. The aim of this study was to assess cancer risks in p.Arg112dup carriers and their first degree relatives (FDRs) and second degree relatives (SDRs). Methods In this prospective cohort study, cancer diagnoses in carriers (n=120), non-carriers (n=111), carriers’ FDRs (n=275) and SDRs (n=321) and controls (n=3976) were obtained from the Swedish Cancer Registry. Relative risks (RRs) for cancers were calculated (number of cancers/person years). Two-sided 95% CIs were calculated for all RRs. Results In carriers prospective RR for non-melanoma cancers was 5.0 (95% CI 3.7 to 7.3), for pancreatic cancer 43.8 (95% CI 13.8 to 139.0), for cancers in upper digestive tissues 17.1 (95% CI 6.3 to 46.5), and in respiratory tissues 15.6 (5.4 to 46.0). In FDRs and SDRs RRs were significantly elevated for cancers in pancreas, respiratory and upper digestive tissues. In ever-smoking carriers compared with never-smoking carriers, the odds ratio (OR) of cancers in pancreas, respiratory or upper digestive tissues was 9.3 (95% CI 1.9 to 44.7). Conclusions CDKN2A p.Arg112dup mutation carriers from melanoma-prone families and their FDRs and SDRs have elevated risk for pancreatic, lung, head and neck and gastro-oesophageal carcinomas. These cancers were mainly seen in ever-smoking carriers. Germline CDKN2A mutations may confer an increased sensitivity to carcinogens in tobacco smoke. CDKN2A mutation carriers should be counselled to abstain from smoking.Journal of Medical Genetics 06/2014; 51(8). DOI:10.1136/jmedgenet-2014-102320 · 6.34 Impact Factor
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